The hypothalamic-pituitary-adrenal (HPA) axis mediates many adaptations to stress, and HPA dysfunction occurs in depression and other stress-related disorders. During pregnancy, HPA-related mechanisms mediate stress-related communication between the maternal and fetal compartments through the placenta, which secretes corticotrophin-releasing hormone (CRH). The overarching hypothesis guiding Project 2 is that fetal and encoding key components of the hypothalamic-pituitary-adrenal (HPA) axis substantially influence fetal vulnerability to intrauterine exposures and maternal emotional distress by modulating (i) the sensitivity of the fetus to the milieu, and (ii) fetal-maternal communication mediated by the placenta. We will use family-based association methods (FBAT and PBAT) to address that hypothesis, by pursuing' the following Specific Aims: (1) examine the effects of maternal stress and fetal genotypes on placental expression of HPA-related genes, (2) examine the relationship among fetal polymorphisms in HPA-related genes and maternal and fetal serum concentrations of CRH, CRHBP and cortisol, (3) test the association of fetal genotypes and haplotypes of HPA-axis related genes with fetal and neonatal outcome (uterine blood flow, birth weight and infant cortisol response after inoculation and strange situation), and (4) test for gene x environment interactions, the environment being low vs. high maternal stress during pregnancy on the outcomes examined in Specific Aims 2 and 3. Public-health relevance: Increasing evidence suggests that maternal depression and other stress-related disorders occurring during pregnancy negatively impact fetal and infant outcomes. HPA-related mechanisms appear to be critical mediators and modulators of the relationship between maternal stress and depression, and such outcomes. Understanding whether and how variation at specific HPA-axis-related genes alters the vulnerability of offspring to maternal stress and depression may elucidate the role of the gene products they encode in negative (and positive) fetal and infant outcomes. Such knowledge will facilitate early-intervention strategies for at-risk children, and their mothers.